1. Field of the Invention
The present invention relates to a novel porphyrin compounds such as a porphyrin metal complex, an albumin inclusion compound thereof, and an artificial oxygen carrier.
2. Description of the Related Art
Heme, i.e., a porphyrin iron (II) complex, constituting the active center of hemoglobin or myoglobin that plays the role of carrying and storing oxygen within the living body, is capable of reversibly adsorbing and desorbing molecular oxygen in response to oxygen partial pressure.
Many researches have been reported since 1970's in an effort to achieve the oxygen binding and dissociating capability similar to that performed by natural heme by using a synthetic porphyrin iron (II) complex. As forerunner researches, for example, J. P. Collman, Acc. Chem. Res., 10, 265 (1977) and F. Basolo, B. M. Hoffman, J. A., ibers, Acc. Chem. Res., 8, 384 (1975) can be cited. Particularly, 5,10,15,20-tetrakis(α,α,α,α-pivalamidophenylporphyrin iron (II) complex (hereinafter referred to as “FeTpivPP complex”) is known as a porphyrin iron (II) complex that is reported to be capable of forming an oxygen complex that is stable under room temperature conditions (see J. P. Collman, et al., J. Am. Chem. Soc., 97, 1427 (1975). The FeTpivPP complex is capable of reversibly adsorbing and desorbing the oxygen molecule at room temperature within an organic solvent such as benzene, toluene, dichloromethane, tetrahydrofuran or N,N-dimethylformamide, if an excess amount of an axial base such as 1-alkylimidazole or 1-alkyl-2-methylimidazole is co-present. Also, if the complex is encapsulated in a bi-layer vesicle made of a phospholipid, the complex similarly exhibits an oxygen binding and dissociating capability even under the physiological conditions (aqueous system, pH 7.4, ≦40° C.). (see E. Tsuchida et al., J. Chem. Soc., Dalton Trans., 1984, 1147 (1984)).
However, in order to allow the FeTpivPP complex to bind oxygen reversibly, it is necessary to add an excess molar amount of the axial base compound from the outside as pointed out above. Some imidazole derivatives widely used as the axial base may produce a pharmaceutical effect and may exhibit a high toxicity in the living body. Also, in the case of utilizing a phospholipid vesicle, the imidazole derivative that is co-present in an excess amount may make the vesicle unstable. To ultimately decrease the addition amount of the axial base is to introduce the imidazole derivative into the porphyrin molecule by the covalent bond.
The research group including the present inventors have took the position that a stable oxygen carrier can be provided without externally adding the axial base, if an imidazole is covalently bonded, as a side chain substituent, to the porphyrin iron (II) complex. Based on the particular idea, a FeTpivPP analogue having a substituent in the 2-position of the porphyrin ring have been accurately synthesized. Further, an inclusion compound having the FeTpivPP analogue included in the phospholipid vesicle or the human serum albumin has been prepared, providing an artificial oxygen carrier capable of reversibly adsorbing and desorbing oxygen (see Japanese Patent Disclosure (Kokai) No. 59-164791, Japanese Patent Disclosure No. 59-162924, Japanese Patent Disclosure No. 6-271577 and Japanese Patent Disclosure No. 8-301873).
However, most of the synthetic porphyrin iron (II) complexes capable of forming a stable oxygenated complex nowadays are tetraphenylporphyrin iron complexes such as the FeTpivPP analogue. Derivatives having a proximal base covalently bonded to the protoporphyrin iron (II) complex, which constitutes the active center of hemoglobin or myoglobin within the living body, have been synthesized (see W. S. Brinigar, C. K. Chang, J. Geibel, T. G. Traylor, J. Am. Chem. Soc., 96, 5597 (1974)). However, these derivatives tends to readily form a μ-oxo dimer even within an organic solvent such as N,N-dimethylformamide or toluene and, thus, the stability of its oxygenated complex is low, as compared to the tetraphenylporphyrin iron (II) complex. The group of the present inventors have also synthesized a derivative in which an alkylimidazole is covalently bonded to the protoporphyrin iron complex, and prepared an oxygenated complex in respect of the compound having the above-noted derivative included in albumin (see above mentioned Japanese Patent Disclosure No. 8-301873). However, the half-life period of its oxygenated complex is not longer than one hour under 25° C. It follows that the oxygenated complex leaves room for further improvement in terms of the stability in the case of using the oxygenated complex as an artificial oxygen carrier.
Needless to say, the protoporphyrin iron complex derivative is advantageous also in the case where the administration into the living body is taken into account. Protoporphyrin iron (III) that has been no longer utilized in the living body is caught by heme oxidases so as to cleave the α-meso position of the porphyrin and thus is decomposed into biliberdin so as to be used in the metabolic process. Since the hydrogen atom in the meso position is substituted with the phenyl ring in the tetraphenylporphyrin iron complex, the tetraphenylporphyrin iron complex may not be decomposed in the metabolic mechanism.
Thus, in the case of considering the use of an aqueous dispersion of a synthetic porphyrin iron (II) complex as an artificial oxygen carrier, e.g., as a substitute for the erythrocyte, development of a molecule design and synthesis of a porphyrin iron derivative capable of forming an oxygenated complex having a higher stability and development of an inclusion compound having the particular porphyrin ion derivative included therein are strongly desired.